Passive immunization with antibodies to cryptococcal polysaccharide targets an essential virulence factor of Cryptococcus neoformans and has the potential to directly address several deficiencies and treatment problems that occur in the patient with AIDS. In preliminary experiments, we have produced a hybridoma which secretes a monoclonal antibody reactive with an epitope shared among the capsular polysaccharides of all serotypes of the yeast. Thus, the antibody has an ideal specificity for use in passive immunization. This monoclonal antibody is of the IgG1 subclass. Heavy-chain isotype-switch variants secreting antibodies of the IgG2b and IgG2a isotypes were sequentially isolated by sib selection from the parent IgG1-secreting line. These antibodies have identical reactivity with cryptococcal polysaccharide but differ in the biological activities attributable to the Fc region of the antibody. The isotype-switch family of antibodies was examined for the ability to opsonize the yeast and to passively immunize mice challenged with viable cryptococci. The opsonic activity of the antibodies varied with the isotype, with IgG2a>IgG1>IgG2b. The antibodies have been used prophylactically and therapeutically in an effort to alter the course of murine cryptococcosis. Passive immunization with the IgG2a and IgG2b antibodies effected a substantial reduction in numbers of cryptococci in lung and spleen. The IgG2b antibody was particularly effective, producing a 10- to 100-fold reductions of viable cryptococci in these tissues. We propose to examine further the in vivo ability of passive immunization to alter the course of experimental cryptococcosis. Initial studies will determine the optimal conditions needed for passive immunization with anticryptococcal antibodies of the IgG1, IgG2a, and IgG2b isotypes. Variables to be examined include i) antibody dose, ii) serum antibody concentrations needed for treatment, iii) route of passive immunization, and iv) significance of circulating cryptococcal antigen. Factors which might influence and minimize toxicity associated with passive immunization will be identified. Relevant questions include i) the mechanism of toxicity, ii) the role of immunoglobulin isotype in toxicity, and iii)the ability of pharmacologic modulators to block toxicity. Finally, the ability of the isotype-switch family of antibodies to improve the efficacy of conventional and experimental anticryptococcal therapy will be determined.